Abstracts from the Thirteenth International Symposium on Pediatric Neuro-Oncology
Authors: Diane Birks, Andrew Donson, Sean Mcnatt, Nicholas Foreman, Michael Handler, Hidehiro Oka, Kiyotaka Fujii, Lucie Lafay-Cousin, Daniel Keene, Anne-Sophie Carret, Bruce Crooks, David Eisenstat, Chris Fryer, Donna Johnston, Valerie Larouche, Albert Mograbi, Beverly Wilson, Anthony Whitton, Shayna Zelcer, Eric Bouffet, Ramon Navarro, Astrid Laguna, Noelia Pérez, Carmen De Torres, Parareda Andreu, Jaume Mora, Ofelia Cruz, Robert Sanders, Paula Schaiquevich, Frederick Boop, Deborah Ward, Zoltan Patay, Amar Gajjar, Clinton Stewart, Ai Muroi, Shingo Takano, Takashi Fukushima, Tetsuya Yamamoto, Atsushi Saito, Akira Matsumura
Journal: Neuro-Oncology (2008)

Atypical teratoid/rhabdoid tumors (AT/RTs) are highly aggressive malignant CNS tumors of early childhood.Prognosis is extremely poor with median survival times ranging from 6 to 17 months.It has been recognized since the late 1990s that both AT/RTs and malignant rhabdoid tumors of the kidneys and other soft tissues are characterized by a loss of INI1 (aka SMARCB1, BAF47, hSNF5), a component of the SWI/SNF protein complex that regulates transcriptional activity through chromatin remodeling.In fact, loss of INI1 protein, as determined through immunohistochemistry, has become the de facto standard for diagnosis of AT/RTs.Any pediatric brain tumor showing loss of INI1 will generally be diagnosed as an AT/RT, regardless of histological characteristics.However, loss of INI1 has been found in other tumor types, including schwannomas and epithelioid sarcomas.Also, INI1 is not absent in approximately 15% of pediatric brain tumors that show diagnostic histological features for AT/RTs.Thus, INI1 may not be wholly specific to malignant rhabdoid tumors or AT/RTs.To identify potential diagnostic markers specific to AT/RT, 110 pediatric and adult brain tumor samples and 66 normal brain samples were analyzed for gene expression using Affymetrix U133Plus2 GeneChip microarrays.These arrays measure the expression of .54,000probe sets, including all known human genes.The tumor samples analyzed included eight AT/RTs, as well as glioblastoma, medulloblastoma, large-cell medulloblastoma, ependymoma, pilocytic astrocytoma, rhabdomyosarcoma, meningioma, and radiation-induced tumors.AT/RT expression was compared individually to each other tumor type as well as to normal samples; p-values were adjusted using a false discovery rate of 0.05 which took into account all tests both within and across all groups.Fifty-nine unique genes were found to be overexpressed in the AT/RT samples when compared to all other groups (including normal); five genes were underexpressed.While generally INI1 was expressed at lower levels in AT/RTs than in all other samples, this did not achieve statistical significance for two groups (normal and meningioma).This result is not surprising, because microarrays measure mRNA levels rather than protein levels.Of the 59 genes statistically overexpressed in AT/RTs, 58 showed overlap in their range of expression with other tumor types.However, one gene was found that was consistently expressed in AT/RTs but showed almost no overlap in its range of expression compared to the tumor or normal samples: claudin 6 (CLDN6), a key component of tight junctions.There was an average difference of .50-fold between CLDN6 levels in AT/RTs versus all other tumors and similarly versus normal samples.Compared to medulloblastomas, the most difficult tumor type to discriminate from AT/RTs, CLDN6 was expressed .53-fold higher in AT/RTs with no overlap at all in expression levels.Analysis of protein abundance using Western blotting confirmed the microarray results.Thus the combination of INI1 as a negative marker and CLDN6 as a positive marker may be useful in defining AT/RTs for diagnostic purposes.